1. Field of the Invention
The invention relates to pharmaceutical formulations of thioctic acid and the enantiomers thereof. Formulations according to the invention are used for the production of pharmaceutical dosage forms which release the active ingredient more rapidly and have greater bioavailability than previous dosage forms.
2. Description of the Related Art
Thioctic acid (xcex1-lipoic acid) is chemically 1,2-dithia-cyclopentane-3- valeric acid. The production of free R-thioctic acid is described, for example, in DE-OS 41 37 773.
Thioctic acid is a component of cell metabolism and is thus found in many plants and animals. It acts as one of the coenzymes during oxidative decarboxylation of pyruvate and other xcex1-keto acids. Thioctic acid has been used for some time in various conditions, for example, inter alia, in liver conditions, in liver damage due to fungal poisoning and in diabetic and alcoholic polyneuropathy, a degeneration of the peripheral nerves which accompanies metabolic disorders.
The present invention relates to pharmaceutical formulations containing thioctic acid or solid salts of thioctic acid with improved bioavailability.
This invention relates not only to the racemic form, but also to the pure (R)- or (S)-thioctic acid as well as to mixtures of (R)- and (S)-thioctic acid of any desired composition. Of the pure optical isomers of thioctic acid (R- and S-form, i.e. R-thioctic acid and S-thioctic acid), unlike the racemate, the R-enantiomer has a predominantly anti-inflammatory action and the S-enantiomer has a predominantly anti-nociceptive action, wherein the anti-inflammatory action of the R-enantiomer is, for example, stronger than that of the racemate by a factor of 10.
The anti-nociceptive (analgesic) action of the S-enantiomer is, for example, stronger than that of the racemate by a factor of 6.
Thus, in comparison with the racemate, the enantiomers are much more specific and effective active ingredients.
The actions are described in EP 427 246 and EP 427 247 and in GbM 90 17 987.0 and EP 530 446.
A combination of thioctic acid with vitamins is described in EP 572 922.
R,S-Thioctic acid has a melting point of 60.5xc2x0 C. R-Thioctic acid has a melting point of 50.6-50.7xc2x0 C. Both are soluble at 25xc2x0 C. in water at a rate of 12.14 mg/10 ml and in methanol, ethanol, chloroform, dimethylformamide and n-octanol at a rate of above 1000 mg/10 ml.
In comparison with parenteral dosage forms, orally administrable pharmaceutical preparations have a price advantage, which has a favorable effect on daily therapeutic costs. However, previous dosage forms of thioctic acid have the disadvantage of having relatively low bioavailability. Low bioavailability means that, on oral administration of the dosage form, in comparison with intravenous administration, relatively little of the unaltered active ingredient is found in the blood of the test subject or patient. As a consequence, oral administration of the medication cannot be as effective as intravenous administration of the active ingredient. There is thus an object of developing dosage forms which, together with good storage stability, have the greatest possible bioavailability.
The present invention provides dosage forms of thioctic acid and solid salts thereof having increased bioavailability in comparison with previous dosage forms. The increased bioavailability is surprisingly achieved by preparing the active ingredient in a form resistant to gastric juice, which, once it has passed into the duodenum, rapidly dissolves at the pH value of the intestinal juice. The pH value of the intestinal juice is 6.8 to 7.3. The active ingredient which may be used here is either the free thioctic acid orxe2x80x94more advantageouslyxe2x80x94a salt of thioctic acid.
The poor release of the active ingredient R-thioctic acid from the dosage forms prepared therefrom is disadvantageous. On release testing according to the Deutsches Arzneibuch [German pharmacopoeia], 10th edition (paddle agitator method) or USP XXII [United States pharmacopeia, 22nd Edition] with apparatus 2), release of the active ingredient from tablets according to Example 2a, using 0.06 N HCl as release medium at 37xc2x0 C., is as follows:
after 15 minutes: 6%
after 30 minutes: 9%
disintegration time:  less than 2 min.
This is in contrast with the behaviour of tablets prepared from the racemate of thioctic acid, which, with the same composition of the tablets, exhibit the following active ingredient release (method as above):
after 15 minutes: 99%
after 30 minutes: 100%
disintegration time: 2.5 min.
It was surprisingly found that when solid salts of R-thioctic acid were used to produce the tablets according to Example 3, good release values were again obtained (method as above):
after 15 minutes: 75%
after 30 minutes: 88%
disintegration time:  less than 1 min.
Salt formers which may, for example, be considered are conventional bases or cations which are physiologically compatible in salt form. Examples of such substances are:
alkali or alkaline earth metals, such as sodium, potassium, calcium, magnesium;
ammonium hydroxide;
basic amino acids, such as, for example, ornithine, cystine, methionine, arginine and lysine;
amines of the formula N R1 R2 R3, in which the residues R1, R2 and R3 are identical or different and mean hydrogen, C1-C4 alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, or C1-C4 oxyalkyl, such as, for example, mono- and diethanolamine, 1-amino-2-propanol, 3-amino-1-propanol;
alkylenediamines with an alkylene chain of 2 to 6 C atoms, such as, for example, ethylenediamine or hexamethylene-tetramine; and
saturated cyclic amino compounds with 4 to 6 ring carbon atoms, such as, for example, piperidine, piperazine, pyrrolidone, morpholine; N-methylglucamine, creatine and tromethamine.
The salt formers have already been mentioned in the above-stated patents in general terms, but production of the salts and the particular suitability thereof for the production of certain dosage forms is not discussed. Liquid dosage forms with the tromethamine, lysine and ethylenediamine salt of R-thioctic acid are described in various patent applications, for example in EP 427 246, EP 427 247, EP 530 446.
However, these are without exception solutions in which the salt is formed in solution by combining R-thioctic acid and the appropriate base. The salt itself is not isolated and is thus not in crystalline form. Furthermore, the base is generally used in excess, such that it would not be possible to isolate a pure salt.
Salts of R-thioctic acid with L-lysine and L-arginine are mentioned in Spanish patent 313 056. However, there is no information relating to the production and characterisation of the salts nor any mention of better release and bioavailability of the active ingredient from the dosage forms produced therefrom.
Dosage forms of the racemic thioctic acid with improved bioavailability may also be achieved by their containing the solid salts of thioctic acid instead of the previously used free acid. Here too, bioavailability is surprisingly increased in comparison with the dosage form with the free thioctic acid. The above-stated salt formers may be used as the salt former in this case too. Dosage forms with these solid salts for oral administration are novel and have not hitherto been described. While the salt formers have indeed already been mentioned in general terms in various patents, there has been no discussion of their particular suitability for the production of certain dosage forms.
The present invention also provides all dosage forms containing solid salts of R-thioctic acid which are distinguished by better active ingredient release and better bioavailability than dosage forms prepared from R-thioctic acid. In contrast with the dosage forms prepared from free R-thioctic acid, the dosage forms prepared from salts of R-thioctic acid have not only the advantage of better release and bioavailability of the active ingredient, but are moreover more easily produced:
When producing dosage forms from R-thioctic acid, due to the active ingredient""s low melting point of 50.6-50.70xc2x0 C., the active ingredient is readily sintered both during production of the mouldings and during further processing, for example when applying a taste-masking coating. Sintering of the active ingredient, for example when using slightly elevated temperatures, as are necessary for drying and solidifying the coating, leads to a reduction in porosity, in extreme cases even to complete sintering of the moulding. As a consequence, the moulding (tablet, pellet, granule) dissolves only extremely slowly in the gastro-intestinal tract. This also results in poor bioavailability of the active ingredient. When R-thioctic acid salts are used, there is no sintering and consequently no impairment of bioavailability.
The tendency of free R-thioctic acid to sinter during tablet pressing moreover results in the tablets sticking to the punch if tablets with a relatively high active ingredient content are to be produced on an industrial scale. This may even mean that pressing operations have to be interrupted.
Simultaneously solving the problems of poor active ingredient release and complicated production of dosage form by using the salts of R-thioctic acid instead of the free R-thioctic acid is surprising.
It should be noted in this connection that the two problems of disintegration and dissolution are not directly associated with each other: despite good disintegration behaviour, perfect tablets without sintering phenomena exhibit poor release of the active ingredient R-thioctic acid, as was shown by the above example.
Dosage forms for the salts of R-thioctic acid which may be mentioned are not only tablets, granules, inhalation powders, hard gelatine capsules and pellets, but also soft gelatine capsules, metered aerosols, suspensions, ointments and suppositories, in which the salt is incorporated into a base material, for example into amphiphilic or lipophilic media, polyethylene glycol or propellants.
In comparison with R-thioctic acid, better release from the base material may also be observed in the last-mentioned dosage forms.
The present invention also provides dosage forms containing solid salts of R-thioctic acid. The dosage forms may be used either as a pharmaceutical preparation or as a food additive. The salts may be formed from the salt formers described above and R-thioctic acid. Salts prepared from R-thioctic acid and tromethamine, L-lysine, L-arginine, sodium hydroxide, ammonium hydroxide and creatine are particularly preferred. Production is performed using methods which are generally known in the prior art, as are, for example, described in connection with the racemate of thioctic acid in DE-OS 16 95 358, French patent 4630 M or Example 1.
Analytical values for some of the particularly preferred salts are:
A further advantage may be exploited when optically active salt formers are used:
It is possible to react racemic thioctic acid with the optically active salt former to yield the R- and S-thioctic acid salts. Due to their differing properties, these may be separated and then directly further processed into the dosage forms, wherein it is possible to dispense with any release of R- or S-thioctic acid. Salt formers which may, for example, be used are: L-lysine, L-arginine, D(xe2x88x92)-N-methylglucamine.
The dosage forms are produced using the standard methods which are conventional for this purpose, as are, for example, described in the standard work Sucker, Fuchs, Speiser Pharmazeutische Technologie, Thieme Verlag Stuttgart, 1978.
Gastric juice resistance of the dosage forms is achieved either by encapsulating the active ingredient in anionic polymers, for example with a pKA value of 5.0 to 5.5, and subsequently producing appropriate dosage forms using this encapsulated material. The conventional method for achieving gastric juice resistance of formulations is, however, to coat them with anionic polymers, for example with a pKA value of 5.0 to 5.5, which do not begin to dissolve until a minimum pH value of 5.0.
Such substances which may be cited by way of example are: shellac, hydroxypropylmethyl cellulose phthalate (commercial product, for example HP 55, manufacturer: Shinetsu Chemical Company, Tokyo), cellulose acetate phthalate (commercial product, for example Aquateric, manufacturer: FMC Export Corporation, Philadelphia, USA), polyvinyl acetate phthalate, copolymers prepared from methacrylic acid and methacrylic acid esters (commercial products, for example Eudragit L and Eudragit S grades together with Eudragit L 30 D, manufacturer: Rxc3x6hm Pharma). The dosage forms are produced using the standard methods which are conventional for this purpose, as are for example described in the standard work Sucker, Fuchs, Speiser Pharmazeutische Technologie, Thieme Verlag Stuttgart, 1978, and in Bauer, Lehmann, Osterwald Rothgang xc3x9cberzogene Arzneiformen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1988.
Gastric juice resistance is tested using USP XXII method  less than 701 greater than  Disintegration, wherein the dosage forms must have a resistance to synthetic gastric juice of over two hours, but at least of over 30 minutes.